1. Field
The present disclosure relates to an anticancer supplement agent that can be used in combination during anticancer therapy or radiation therapy, to enhance apoptotic effects on a cancer cell during therapy.
2. Description of the Related Art
In consideration of cancer treatment, surgery, radiation therapy, anticancer therapy, and the like have been widely used, and if necessary, such therapy may be used in combination. About 35% of patients with cancer in Korea and about 50% of patients with cancer in U.S.A have been receiving radiation therapy. According to a trend increasing a number of patients who receive radiation therapy every year, importance of radiation therapy is also more considered. In the case of cancer therapy by surgery, such a surgical treatment may be used in combination with radiation therapy and anticancer therapy, so that recurrence of cancer or metastasis may be inhibited. In this regard, use of high-dose radiation therapy or anticancer agents with high dosage is required, but in reality, dose or dosage of the radiation or the anticancer agent, respectively, is limitedly used in consideration of side effects, such as inflammation or necrosis of a topical region, damage on a normal tissue, or toxicity of an anticancer agent upon systematic drug administration. In addition, as a method of solving problems with resistance or tolerance to anticancer therapy or radiation therapy and minimizing a damage of a normal tissue to enhance cancer therapeutic effects, use of an enhancer or a supplement agent for anticancer therapy and radiation therapy is now more considered.
Cancer cells secrete more antioxidant enzymes, which are capable of removing reactive oxygen species (ROS), than normal cells, and accordingly, cancer cells have a tolerance to radiation of radiation therapy and an anticancer agent of anticancer therapy. In most cases, expression of an antioxidant enzyme is controlled by a transcription factor, nuclear factor E2-related factor 2 (Nrf2). Under normal conditions without oxidative stress, Nrf2 binds to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, resulting in proteasomal degradation. Under oxidative stress such as exposure to radiation, Nrf2 separated from Keap1 translocates into the nucleus and binds to an antioxidant response element (ARE) present within a promoter of an antioxidant enzyme gene, resulting in the expression of various antioxidant enzymes to remove oxidative stress. However, in cancer cells, especially cells of lung cancer and prostate cancer, without oxidant stress, mutations of the Nrf2 gene may occur, resulting in continuous expression of the Nrf2 gene. Alternatively, mutations of a Keap1 gene that is antagonistic to the Nrf2 gene may occur, resulting in loss of the Keap1 gene function, and in this regard, Nrf2 may move into a nucleus for over-expression of the antioxidant enzyme.
In addition, in the case of radiation therapy, activity of Nrf2 can be further enhanced to remove ROS.
Increase in the number of electrophiles of an anticancer agent or in activity of the Nrf2 transcription factor according to ROX signals of the radiation may interfere with cancer therapeutic effects by anticancer therapy and radiation therapy. In particular, the Nrf2 transcription factor in cells of lung cancer is consistently activated, so that cancer treatment is known to be very difficult.
Doxorubicin (as known as adriamycin) as a topoisomerase II inhibitor causes generation of ROS and is an anticancer agent having an action mechanism of damaging the DNA of cancer cells. Doxorubicin is significantly effective in the treatment of not only solid cancer, e.g., lung cancer and colorectal cancer, but also blood cancer, e.g., leukemia. However, cancer cells with the increased activity of the Nrf2 transcription factor may induce the expression of the antioxidant enzyme, e.g., heme oxygenase-1 (HO-1) that can offset the action mechanism of doxorubicin by the Nrf2 transcription factor, resulting in doxorubicin-resistant cancer cells. In this regard, if the activity of Nrf2 is inhibited in an efficient manner, the resistance of the cancer cell to doxorubicin may be reduced, thereby enhancing anticancer effects.
As described above, the activation of Nrf2 is considered as a main cause of cancer cell's resistance to anticancer agent therapy or radiation therapy. Therefore, research about identifying a Nrf2 inhibitor and about developing a combined treatment for the enhancement of apoptosis of the cancer cells through chemotherapy or radiation therapy in combination with the cancer cells is demanded.